Medicine (RMH) - Theses
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ItemPost-reperfusion pathophysiology and secondary injury in ischemic stroke( 2021)Stroke is the second most common cause of death and third leading cause of long-term disability worldwide. The majority of strokes are due to arterial occlusions causing cerebral ischemia, where urgent restoration of blood flow is the primary goal of acute treatment. However, nearly 40% of patients nevertheless develop significant disability, even when occluded vessels are rapidly recanalized. This failure to improve from seemingly successful intervention is not well understood. In addition to injury already established pre-treatment, other subsequent pathological mechanisms may compromise the benefit of reperfusion. Adverse events after reperfusion causing additional cerebral injury may be an important but underappreciated factor contributing to poor outcome. Overt clinical manifestations of secondary injury include malignant cerebral edema and symptomatic intracerebral hemorrhage. Experimental studies suggest post-stroke inflammation and microvascular dysfunction are involved in perpetuating injury even after blood flow is restored to ischemic tissue. This thesis uses neuroimaging to explore pathophysiological processes after reperfusion that may contribute to unfavorable outcomes in patients with acute ischemic stroke. The first component of the thesis studies the effect of ischemia and reperfusion on cerebral tissue, re-examining the conventional approach of dichotomizing tissue fate as either infarcted or salvaged. Using cerebral edema as a clinical example of secondary injury, the thesis then explores factors involved in the development of post-stroke cerebral edema. How tissue may respond differently to reperfusion, and whether reperfusion may be paradoxically detrimental in humans is studied. Comparison of imaging markers currently used to measure cerebral edema is performed. Finally, the thesis investigates persistent tissue perfusion abnormalities in patients with apparently successful intervention. Better understanding of pathophysiological processes contributing to adverse outcomes after reperfusion may offer potential avenues to improve the efficacy of current reperfusion treatments. Identifying imaging correlates of these processes may help prognostication in clinical practice and improve patient selection for future trials targeting secondary injury.
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ItemGlutamate as a biomarker of post-stroke epilepsy( 2021)Stroke is one of the most important causes of acquired epilepsy in adults. Patients with seizures after stroke have higher mortality and disability than those without seizures. There is a building body of evidence to suggest that post-stroke epilepsy may be mediated by dysregulation of glutamate homeostasis, given the central role of glutamate in the pathogenesis of both stroke and seizures. There is currently no evidence to support the use of antiseizure medications as primary prevention of epilepsy in stroke patients. Ideally, anti-epileptogenic treatment would be targeted at those stroke patients at highest risk of epilepsy according to established biomarkers – studying glutamate as one such biomarker has been limited by a reliance on invasive procedures including lumbar puncture to quantify concentrations of glutamate in the brain. This thesis focuses on the role of 7T MRI as a method of brain glutamate quantification in the setting of stroke. The research has been conducted in the Department of Neurology, Royal Melbourne Hospital, the Department of Medicine (The Royal Melbourne Hospital), University of Melbourne, and the Melbourne Node of the National Imaging Facility, Department of Radiology, University of Melbourne. 22 patients with acute ischaemic or haemorrhagic stroke were recruited from the inpatient stroke unit at Royal Melbourne Hospital, with 7T MRI scans performed at the Melbourne Brain Centre Imaging Unit, University of Melbourne. In addition, peripheral blood samples were collected and underwent metabolomics analysis for plasma glutamate quantification at the Monash Institute of Pharmaceutical Sciences, Parkville. Across the patient cohort, glutamate concentration was lower in the region of infarction than in the corresponding hemisphere, when measured by Magnetic Resonance Spectroscopy. When measured by glutamate weighted chemical exchange saturation transfer imaging (GluCEST), the results were more heterogeneous, ranging from decreased to increased, ipsilateral to infarction. One patient in the cohort developed post-stroke epilepsy, with a GluCEST profile similar to the population overall. A single haemorrhagic stroke patient suffered a seizure prior to scan acquisition, with a pattern of increased cortical GluCEST contrast consistent with a post-seizure effect. The second part of the thesis focuses on a study protocol examining the anti-epileptogenic potential of the glutamate receptor antagonist and antiseizure medication perampanel in a population at high risk of post-stroke epilepsy. This involves a collaboration of clinicians at four Melbourne Hospitals (Alfred Hospital, Royal Melbourne Hospital, Monash Medical Centre, Austin Hospital), led by the candidate. Finally, there is evidence that patients with epilepsy have an increased risk of developing cerebrovascular or cardiovascular disease, although it is unclear whether this is due primarily to the epilepsy itself, or non-epilepsy factors such as antiseizure medications. The third part of the thesis comprises a data linkage study in the Department of Neurology, Royal Melbourne Hospital, based on medical records from a database of admitted video EEG monitoring patients from 1995 to 2015. It was found that the incidence of new-onset cerebrovascular disease was higher in epilepsy patients compared with the general Victorian population, although there was no difference in the composite incidence of cerebrovascular disease, cardiovascular disease and peripheral vascular between epilepsy and non-epilepsy patients in the cohort. Furthermore, patients taking treatment with valproic acid were at lower risk than both those taking enzyme-inducing antiseizure medications and those taking neither valproic acid nor enzyme-inducing antiseizure medications. Collectively, these results emphasise the role of non-epilepsy factors such as social determinants of health, medical comorbidity, and epilepsy treatment, in influencing vascular risk.
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ItemTransforming pre-hospital care of stroke( 2020)Stroke is the second leading cause of death, as well as the second leading cause of disability worldwide. In Australia, the estimated financial burden of stroke on direct healthcare costs and healthy life lost is upwards of $50 billion Australian dollars annually. Highly effective reperfusion therapies exist to improve outcomes for ischaemic stroke but must generally be administered within the first few hours of stroke onset to ensure salvageable tissue is still present. Similarly, most haematoma expansion in intracerebral haemorrhage occurs early and promising interventions are being investigated to potentially reduce growth in this hyperacute period. The journey of a patient from stroke onset through to paramedic management, transport to hospital and eventual treatment is complex, with many workflow steps both in the pre-hospital and in-hospital phases that are susceptible to delays. This means that effective acute interventions in stroke may be delayed or may not be available to a proportion of patients. Historically, much of the effort for improving time to treatment has focussed largely on optimisation of in-hospital workflows. However, the pre-hospital phase may account for up to 50% of the time from stroke recognition to treatment. This is even greater if patients require a secondary inter-hospital transfer, should the initial centre not have capability to provide specialised treatments like endovascular thrombectomy or neurosurgery. This thesis explores two complementary methods of improving pre-hospital care of patients suffering from stroke. The first method is optimising ambulance triage of patients to allow direct transport to specialised stroke centres with advanced treatments. This is achieved through paramedic-led assessment of a clinical severity tool to determine patients likely to benefit from endovascular thrombectomy or neurosurgical services. This thesis studies the feasibility of such a system in metropolitan Melbourne, the design of a new triage tool adapted to local needs and validation of the tool in a real-world pre-hospital cohort of stroke patients. The second method is the use of an Australian-first mobile stroke unit, a custom-built ambulance with on-board computed tomography scanner and multidisciplinary stroke team, that allows pre-hospital assessment, imaging, treatment and triage of stroke patients. This thesis explores the operationalisation of the Melbourne Mobile Stroke Unit, the clinical benefits achieved by the service for treatment of both ischaemic and haemorrhagic stroke and the provision of novel therapies in the pre-hospital setting. Future adoption of the two synergistic pre-hospital strategies on a larger scale is expected to deliver substantial benefits to patients with stroke. Those eligible for time-critical treatment will be able to receive such therapies significantly faster, with expected improvements in longer term health outcomes. Improved pre-hospital management minimises the disadvantage experienced by patients located further away from appropriate stroke services, allowing some mitigation of healthcare inequality. Successful implementation in Melbourne will provide a template for roll-out of the strategies nationally and internationally.